Atrial fibrillation (AF) is the most common arrhythmia requiring medical intervention, affecting 2 million people in the United States alone and costing over $6 billion dollars annually. AF results in a 3-5 fold increased stroke risk and a 1.9 fold increased risk of death. Current therapies are incompletely effective, because mechanisms initiating AF are poorly understood. Recent evidence demonstrates abnormal electrical activity from pulmonary veins (PV) initiates some types of AF. Recently, we identified a previously unrecognized cell population in the adult mouse that is confined to the pulmonary veins and portions of the atria. These cells express melanocyte markers, including Dopachrome Tautomerase (Dct), and are electrically excitable, generating action potentials that resemble those recorded in atrial myocytes. We refer to these cells as "cardiac melanocyte-like cells" (CMLCs). Experiments in mice (Dct-/-) lacking the Dct protein, show increased spontaneous and induced atrial arrhythmia when compared to control Dct littermates. Importantly, although Dct-/- hearts are structurally normal and Dct-/- mice have atrial effective refractory periods similar to Dct mice, Dct-/- CMLC action potentials are prolonged. Furthermore, early after-depolarizations (EADs) are prevalent in Dct-/- CMLCs, but not in Dct-/- atrial myocytes, suggesting a critical role for CMLCs in the increased arrhythmogenesis evident in Dct-/- animals. Experiments contained in this proposal are designed to: 1: Characterize the ionic conductances underlying action potential repolarization in CMLCs. 2: Identify the ionic determinants of action potential prolongation in Dct-/- CMLCs. Insights into the roles of CMLCs in regulating cardiac excitability may ultimately result in insights that could lead to the development of novel therapeutic AF treatment strategies. PUBLIC HEALTH RELEVANCE: This project will build upon previous work describing an animal model of atrial arrhythmias. Further work is expected to result in identifying potential new drug targets to for atrial fibrillation treatment.